Abstract

Background. Challenge of MHC-mismatched murine bone marrow chimeras with recipient-type lymphocytes (recipient-lymphocyte-infusion, RLI) produces antileukemic responses in association with rejection of donor chimerism. In contrast, MHC-matched chimeras resist eradication of donor chimerism by RLI. Here, we investigated lymphohematopoietic host-versus-graft reactivity and antileukemic responses in the MHC-matched setting, which is reminiscent of the majority of clinical transplants.

Design and Methods. We challenged C3H→AKR radiation chimeras with AKR-type splenocytes (=RLI) and BW5147.3 leukemia cells. We studied the kinetics of chimerism using flow cytometry and the mechanisms involved in antileukemic effects using in vivo antibody-mediated depletion of CD8+ T and NK-cells, and intracellular cytokine staining.

Results. Whereas control chimeras showed progressive evolution towards high-level donor T-cell chimerism, RLI-chimeras showed a limited reduction of donor chimerism with delayed onset and long-term preservation of lower-level mixed chimerism. RLI chimeras nevertheless showed a significant survival benefit after leukemia challenge. In vivo antibody-mediated depletion experiments showed that both CD8+ T-cells and NK-cells contribute to the antileukemic effect. Consistent with a role for NK-cells, the proportion of IFN-γ-producing NK-cells in RLI-chimeras was significantly higher than in control chimeras.

Conclusion. In the MHC-matched setting, RLI elicits lymphohematopoietic host-versus-graft reactivity that is limited but sufficient to provide an antileukemic effect, and this is dependent on CD8+T-cells and NK-cells. The data indicate that NK-cells are activated as a bystander phenomenon during lymhohematopietic T-cell alloreactivity and thus support a novel type of NK involvement in anti-tumor responses after post-transplant adoptive cell therapy.